Many biopharmaceuticals are produced by genetically modified single cell organisms, known as producer cells. A well established system has been established for producing biopharmaceuticals using mammalian producer cells. The first step involves deriving a high-producing cell line that is suitable for large scale production, a process that involves first transfecting, cloning and then characterising a large number of cell lines. This is an expensive and labour and time intensive process, lasting up to 12 months. Once a gene of interest has been transfected and selection pressure applied using the expression system of choice, the next step involves selection and isolation of cells with acceptable growth and recombinant protein production rate. Cells are cultured and expanded to give clonal populations and once typically hundreds of clonal polulations are established, cell line characterisation takes place.
During the biopharmaceutical production process, the clones are incubated with a cell culture media that is tailored for the specific production process. These media are generally produced commercially in large batches (lots), however due to the complexity of the production process and large number of variables involves, it is not uncommon for there to be compositional variation between batches of the same cell culture media product, which can result in changes of performance in terms of modified growth response or production titer response or product quality attributes or host cell protein production when the media is employed in a biopharmaceutical production process. Currently, the method of testing lots of cell culture media involves an extended culture in the media of interest in parallel with a previous batch. Growth and productivity are compared, and ocassionally product quality would be compared too. Subtle differences may take a while to manisfest themselves and thus may not be apparent in such a short time period and would require a number of generations. This would not be observed with standard methods. A media which is functionally different from its comparitor would be a cause for concern even though other attributes may be consistent. This underlying ‘latent difference’ could cause productivity, instability or other issues down the line, especially when the product is manufactured at scale in a bioreactor over a long time period over multiple generations.
The problem of variability in cell culture media, especially culture media employed in the biopharmaceutical industry, is recognised in the literature and discussed in a number of documents. For example, Boyan Li et al (Biotechnology and Bioengineering, 107(2), 290-301) discuss the problem and disclose the use of Raman spectroscopy combined with chemometrics as a means of rapid characterisation and quality control of complex cell culture media solutions. However, Raman spectrometers and lasers are highly expensive and require specially trained personnel for accurate and reproducible operation. Girard (www.spinnovation-analytical.com/images/stories/press-releases/SPI-JOB-035-article.pdf) discloses the use of nuclear magnetic resonance (NMR) and custom-design NMR databases to rapidly identify and quantitate the compounds present in fermentation media. While this technique would be very accurate and sensitive, NMR machines are extremely expensive and require highly skilled operate. The article “Cell Culture Media—addressing variability in dry powder mammalian cell culture media” (www.drug-dev.com/Main/Back-issues/CELL-CULTURE-MEDIA-Addressing-Variability-in-Dry-P-598.aspx) discusses the problem in variability specifically between different lots of the same brand of media, and discloses a number of benchmarking study that was performed using different analytical methods including a technique that employs NMR, UPLC and PCA analysis to determine differences between different lots of media. As discussed above, while NMR is extremely sensitive and acurate, NMR machines are very expensive and require highly specialised personnel to operate. In addition, these methods are restricted to analysing the chemical constitution of the media.
It is an object of the invention to overcome at least one of the above-referenced problems.